CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

Kelly L. Williams, Simon Topp, Shu Yang, Bradley Smith, Jennifer A. Fifita, Sadaf T. Warraich, Katharine Y. Zhang, Natalie Farrawell, Caroline Vance, Xun Hu, Alessandra Chesi, Claire S. Leblond, Albert Lee, Stephanie L. Rayner, Vinod Sundaramoorthy, Carol Dobson-Stone, Mark P. Molloy, Marka Van Blitterswijk, Dennis W. Dickson, Ronald C. Petersen & 48 others Neill R. Graff-Radford, Bradley F. Boeve, Melissa E. Murray, Cyril Pottier, Emily Don, Claire Winnick, Emily P. McCann, Alison Hogan, Hussein Daoud, Annie Levert, Patrick A. Dion, Jun Mitsui, Hiroyuki Ishiura, Yuji Takahashi, Jun Goto, Jason Kost, Cinzia Gellera, Athina Soragia Gkazi, Jack Miller, Joanne Stockton, William S. Brooks, Karyn Boundy, Meraida Polak, José Luis Muñoz-Blanco, Jesús Esteban-Pérez, Alberto Rábano, Orla Hardiman, Karen E. Morrison, Nicola Ticozzi, Vincenzo Silani, Jacqueline De Belleroche, Jonathan D. Glass, John B J Kwok, Gilles J. Guillemin, Roger S. Chung, Shoji Tsuji, Robert H. Brown, Alberto García-Redondo, Rosa Rademakers, John E. Landers, Aaron D. Gitler, Guy A. Rouleau, Nicholas J. Cole, Justin J. Yerbury, Julie D. Atkin, Christopher E. Shaw, Garth A. Nicholson, Ian P. Blair

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

LanguageEnglish
Article number11253
Pages1-8
Number of pages8
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 15 Apr 2016

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Ubiquitinated Proteins
mutations
Ubiquitin-Protein Ligase Complexes
proteins
Mutation
Cyclins
Chromosomes
Exome
Frontotemporal Dementia
loci
Proteins
Genes
Ubiquitination
Missense Mutation
Neurodegenerative Diseases
Homeostasis
Substrates
homeostasis
sequencing
Genome

Bibliographical note

Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Cite this

Williams, Kelly L. ; Topp, Simon ; Yang, Shu ; Smith, Bradley ; Fifita, Jennifer A. ; Warraich, Sadaf T. ; Zhang, Katharine Y. ; Farrawell, Natalie ; Vance, Caroline ; Hu, Xun ; Chesi, Alessandra ; Leblond, Claire S. ; Lee, Albert ; Rayner, Stephanie L. ; Sundaramoorthy, Vinod ; Dobson-Stone, Carol ; Molloy, Mark P. ; Van Blitterswijk, Marka ; Dickson, Dennis W. ; Petersen, Ronald C. ; Graff-Radford, Neill R. ; Boeve, Bradley F. ; Murray, Melissa E. ; Pottier, Cyril ; Don, Emily ; Winnick, Claire ; McCann, Emily P. ; Hogan, Alison ; Daoud, Hussein ; Levert, Annie ; Dion, Patrick A. ; Mitsui, Jun ; Ishiura, Hiroyuki ; Takahashi, Yuji ; Goto, Jun ; Kost, Jason ; Gellera, Cinzia ; Gkazi, Athina Soragia ; Miller, Jack ; Stockton, Joanne ; Brooks, William S. ; Boundy, Karyn ; Polak, Meraida ; Muñoz-Blanco, José Luis ; Esteban-Pérez, Jesús ; Rábano, Alberto ; Hardiman, Orla ; Morrison, Karen E. ; Ticozzi, Nicola ; Silani, Vincenzo ; De Belleroche, Jacqueline ; Glass, Jonathan D. ; Kwok, John B J ; Guillemin, Gilles J. ; Chung, Roger S. ; Tsuji, Shoji ; Brown, Robert H. ; García-Redondo, Alberto ; Rademakers, Rosa ; Landers, John E. ; Gitler, Aaron D. ; Rouleau, Guy A. ; Cole, Nicholas J. ; Yerbury, Justin J. ; Atkin, Julie D. ; Shaw, Christopher E. ; Nicholson, Garth A. ; Blair, Ian P. / CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. In: Nature Communications. 2016 ; Vol. 7. pp. 1-8.
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abstract = "Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.",
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note = "Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",
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Williams, KL, Topp, S, Yang, S, Smith, B, Fifita, JA, Warraich, ST, Zhang, KY, Farrawell, N, Vance, C, Hu, X, Chesi, A, Leblond, CS, Lee, A, Rayner, SL, Sundaramoorthy, V, Dobson-Stone, C, Molloy, MP, Van Blitterswijk, M, Dickson, DW, Petersen, RC, Graff-Radford, NR, Boeve, BF, Murray, ME, Pottier, C, Don, E, Winnick, C, McCann, EP, Hogan, A, Daoud, H, Levert, A, Dion, PA, Mitsui, J, Ishiura, H, Takahashi, Y, Goto, J, Kost, J, Gellera, C, Gkazi, AS, Miller, J, Stockton, J, Brooks, WS, Boundy, K, Polak, M, Muñoz-Blanco, JL, Esteban-Pérez, J, Rábano, A, Hardiman, O, Morrison, KE, Ticozzi, N, Silani, V, De Belleroche, J, Glass, JD, Kwok, JBJ, Guillemin, GJ, Chung, RS, Tsuji, S, Brown, RH, García-Redondo, A, Rademakers, R, Landers, JE, Gitler, AD, Rouleau, GA, Cole, NJ, Yerbury, JJ, Atkin, JD, Shaw, CE, Nicholson, GA & Blair, IP 2016, 'CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia', Nature Communications, vol. 7, 11253, pp. 1-8. https://doi.org/10.1038/ncomms11253

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. / Williams, Kelly L.; Topp, Simon; Yang, Shu; Smith, Bradley; Fifita, Jennifer A.; Warraich, Sadaf T.; Zhang, Katharine Y.; Farrawell, Natalie; Vance, Caroline; Hu, Xun; Chesi, Alessandra; Leblond, Claire S.; Lee, Albert; Rayner, Stephanie L.; Sundaramoorthy, Vinod; Dobson-Stone, Carol; Molloy, Mark P.; Van Blitterswijk, Marka; Dickson, Dennis W.; Petersen, Ronald C.; Graff-Radford, Neill R.; Boeve, Bradley F.; Murray, Melissa E.; Pottier, Cyril; Don, Emily; Winnick, Claire; McCann, Emily P.; Hogan, Alison; Daoud, Hussein; Levert, Annie; Dion, Patrick A.; Mitsui, Jun; Ishiura, Hiroyuki; Takahashi, Yuji; Goto, Jun; Kost, Jason; Gellera, Cinzia; Gkazi, Athina Soragia; Miller, Jack; Stockton, Joanne; Brooks, William S.; Boundy, Karyn; Polak, Meraida; Muñoz-Blanco, José Luis; Esteban-Pérez, Jesús; Rábano, Alberto; Hardiman, Orla; Morrison, Karen E.; Ticozzi, Nicola; Silani, Vincenzo; De Belleroche, Jacqueline; Glass, Jonathan D.; Kwok, John B J; Guillemin, Gilles J.; Chung, Roger S.; Tsuji, Shoji; Brown, Robert H.; García-Redondo, Alberto; Rademakers, Rosa; Landers, John E.; Gitler, Aaron D.; Rouleau, Guy A.; Cole, Nicholas J.; Yerbury, Justin J.; Atkin, Julie D.; Shaw, Christopher E.; Nicholson, Garth A.; Blair, Ian P.

In: Nature Communications, Vol. 7, 11253, 15.04.2016, p. 1-8.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

AU - Williams, Kelly L.

AU - Topp, Simon

AU - Yang, Shu

AU - Smith, Bradley

AU - Fifita, Jennifer A.

AU - Warraich, Sadaf T.

AU - Zhang, Katharine Y.

AU - Farrawell, Natalie

AU - Vance, Caroline

AU - Hu, Xun

AU - Chesi, Alessandra

AU - Leblond, Claire S.

AU - Lee, Albert

AU - Rayner, Stephanie L.

AU - Sundaramoorthy, Vinod

AU - Dobson-Stone, Carol

AU - Molloy, Mark P.

AU - Van Blitterswijk, Marka

AU - Dickson, Dennis W.

AU - Petersen, Ronald C.

AU - Graff-Radford, Neill R.

AU - Boeve, Bradley F.

AU - Murray, Melissa E.

AU - Pottier, Cyril

AU - Don, Emily

AU - Winnick, Claire

AU - McCann, Emily P.

AU - Hogan, Alison

AU - Daoud, Hussein

AU - Levert, Annie

AU - Dion, Patrick A.

AU - Mitsui, Jun

AU - Ishiura, Hiroyuki

AU - Takahashi, Yuji

AU - Goto, Jun

AU - Kost, Jason

AU - Gellera, Cinzia

AU - Gkazi, Athina Soragia

AU - Miller, Jack

AU - Stockton, Joanne

AU - Brooks, William S.

AU - Boundy, Karyn

AU - Polak, Meraida

AU - Muñoz-Blanco, José Luis

AU - Esteban-Pérez, Jesús

AU - Rábano, Alberto

AU - Hardiman, Orla

AU - Morrison, Karen E.

AU - Ticozzi, Nicola

AU - Silani, Vincenzo

AU - De Belleroche, Jacqueline

AU - Glass, Jonathan D.

AU - Kwok, John B J

AU - Guillemin, Gilles J.

AU - Chung, Roger S.

AU - Tsuji, Shoji

AU - Brown, Robert H.

AU - García-Redondo, Alberto

AU - Rademakers, Rosa

AU - Landers, John E.

AU - Gitler, Aaron D.

AU - Rouleau, Guy A.

AU - Cole, Nicholas J.

AU - Yerbury, Justin J.

AU - Atkin, Julie D.

AU - Shaw, Christopher E.

AU - Nicholson, Garth A.

AU - Blair, Ian P.

N1 - Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2016/4/15

Y1 - 2016/4/15

N2 - Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

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U2 - 10.1038/ncomms11253

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M3 - Article

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JO - Nature Communications

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JF - Nature Communications

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